Pain due to peripheral neuropathy is a common, complication of diabetes that is likely triggered by multifocal hyperglycemic injury of the peripheral nerve. However, mechanisms of this injury are not known, since the systemic effects of diabetic hyperglycemia complicate the direct glucose effects in peripheral nervous system. In the present proposal, we will use a novel animal model of in vivo local and chronic hyperglycemia to test the hypothesis that early mechanical hyperalgesia in diabetes results from hyperglycemia-induced activation of the polyol pathway, leading to impairment of Schwann cell function, damage to paranodal axon-glia contacts, and finally, ectopic discharges of large myelinated primary afferent fibers. To address this hypothesis rats will be surgically implanted with an osmotic minipump and hyperglycemia will be maintained in vivo, chronically and locally in either dorsal root ganglion or a segment of sciatic nerve by perfusion with hyperglycemic solution. Behavioral tests will be conducted to measure mechanical hyperalgesia in the foot innervated by the treated nerve and compared to the contralateral foot. Electrophysiological, biochemical and immunohistological experiments will characterize functional, metabolic and structural nerve changes, respectively, and determine their rote as mechanisms of local hyperglycemia-induced mechanical hyperalgesia. The occurrence of mechanical hyperalgesia will also be compared in a model of streptozotocin-induced diabetes (systemic hyperglycemia). Data collected in this study will advance our understanding of the early pathogenesis of hyperglycemiainduced neuropathic pain symptoms. The results will provide strong support for the idea that diabetic neuropathy may result from a direct and local hyperglycemic damage in peripheral nerve. Of potential clinical significance is that this information may lead to development of new approaches for early detection and diagnosis of developing diabetic neuropathy and novel preventive approaches in the treatment of painful neuropathy. Finally, the animal model of local hyperglycemia developed in this study should be a useful instrument in studies of symptoms of diabetic neuropathy other than mechanical hyperalgesia and, more generally, in studies and tests of the effects of physiologically and pharmacologically active compounds on peripheral sensory function.